Opposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function

Liad Hinden, Majdoleen Ahmad, Sharleen Hamad, Alina Nemirovski, Gergő Szanda, Sandra Glasmacher, Aviram Kogot-Levin, Rinat Abramovitch, Bernard Thorens, Jürg Gertsch, Gil Leibowitz, Joseph Tam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Activation of the cannabinoid-1 receptor (CB1R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of diabetic kidney disease (DKD). However, the CB1R/mTORC1 signaling axis in the kidney has not been described yet. We show here that hyperglycemia-induced endocannabinoid/CB1R stimulation increased mTORC1 activity, enhancing the transcription of the facilitative glucose transporter 2 (GLUT2) and leading to the development of DKD in mice; this effect was ameliorated by specific RPTCs ablation of GLUT2. Conversely, CB1R maintained the normal activity of mTORC1 by preventing the cellular excess of amino acids during normoglycemia. Our findings highlight a novel molecular mechanism by which the activation of mTORC1 in RPTCs is tightly controlled by CB1R, either by enhancing the reabsorption of glucose and inducing kidney dysfunction in diabetes or by preventing amino acid uptake and maintaining normal kidney function in healthy conditions.

Original languageAmerican English
Article number1783
JournalNature Communications
Issue number1
StatePublished - Dec 2022

Bibliographical note

Funding Information:
We would like to thank Prof. Boaz Tirosh for his critical advice on mTORC1 signaling, and Dr. Dinorah Barasch for her technical assistance in LC-MS/MS analysis. This work was supported by an ERC-2015-StG grant (#676841), an Israel Science Foundation (ISF) grant (#158/18), and a JDRF grant (1-INO-2022-1128-A-N) to J.T. The work of G.S. was supported by the National Research, Development and Innovation Office grant NKFI-6/FK_124038.

Publisher Copyright:
© 2022, The Author(s).


  • Animals
  • Diabetic Nephropathies/pathology
  • Kidney/metabolism
  • Kidney Tubules, Proximal/metabolism
  • Mammals
  • Mechanistic Target of Rapamycin Complex 1/genetics
  • Mice
  • Receptor, Cannabinoid, CB1/genetics


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